OmpA: Gating and dynamics via molecular dynamics simulations

Outer membrane proteins (OMPs) of Gram-negative bacteria have a variety of functions including passive transport, active transport, catalysis, pathogenesis and signal transduction. Whilst the structures of ∼ 25 OMPs are currently known, there is relatively little known about their dynamics in different environments. The outer membrane protein, OmpA from Escherichia coli has been studied extensively in different environments both experimentally and computationally, and thus provides an ideal test case for the study of the dynamics and environmental interactions of outer membrane proteins. We review molecular dynamics simulations of OmpA and its homologues in a variety of different environments and discuss possible mechanisms of pore gating. The transmembrane domain of E. coli OmpA shows subtle differences in dynamics and interactions between a detergent micelle and a lipid bilayer environment. Simulations of the crystallographic unit cell reveal a micelle-like network of detergent molecules interacting with the protein monomers. Simulation and modelling studies emphasise the role of an electrostatic-switch mechanism in the pore-gating mechanism. Simulation studies have been extended to comparative models of OmpA homologues from Pseudomonas aeruginosa (OprF) and Pasteurella multocida (PmOmpA), the latter model including the periplasmic C-terminal domain.     

Kinetochore dynamics: how protein dynamics affect chromosome segregation

Protein dynamics generate adaptive cellular architecture. This concept is exemplified by kinetochores, organelles that orchestrate chromosome segregation during mitosis. In this review, we will focus on protein dynamics at kinetochores and discuss how these dynamics impact chromosome motility during mitosis.     

Multiply accelerated ReaxFF molecular dynamics: coupling parallel replica dynamics with collective variable hyper dynamics

ABSTRACT

To tackle the time scales required to study complex chemical reactions, methods performing accelerated molecular dynamics are necessary even with the recent advancement in high-performance computing. A number of different acceleration techniques are available. Here we explore potential synergies between two popular acceleration methods – Parallel Replica Dynamics (PRD) and Collective Variable Hyperdynamics (CVHD), by analysing the speedup obtained for the pyrolysis of n-dodecane. We observe that PRD?+?CVHD provides additional speedup to CVHD by reaching the required time scales for the reaction at an earlier wall-clock time. Although some speedup is obtained with the additional replicas, we found that the effectiveness of the inclusion of PRD is depreciated for systems where there is a dramatic increase in reaction rates induced by CVHD. Similar observations were made in the simulation of ethylene-carbonate/Li system, which is inherently more reactive than pyrolysis, indicate that the speedup obtained via the combination of the two acceleration methods can be generalised to most practical chemical systems.     

Conformational dynamics of RNA-peptide binding: a molecular dynamics simulation study

Molecular dynamics simulations of the binding of the heterochiral tripeptide KkN to the transactivation responsive (TAR) RNA of HIV-1 is presented, using an all-atom force field with explicit water. To obtain starting structures for the TAR-KkN complex, semirigid docking calculations were performed that employ an NMR structure of free TAR RNA. The molecular dynamics simulations show that the starting structures in which KkN binds to the major groove of TAR (as it is the case for the Tat-TAR complex of HIV-1) are unstable. On the other hand, the minor-groove starting structures are found to lead to several binding modes, which are stabilized by a complex interplay of stacking, hydrogen bonding, and electrostatic interactions. Although the ligand does not occupy the binding position of Tat protein, it is shown to hinder the interhelical motion of free TAR RNA. The latter is presumably necessary to achieve the conformational change of TAR RNA to bind Tat protein. Considering the time evolution of the trajectories, the binding process is found to be ligand-induced and cooperative. That is, the conformational rearrangement only occurs in the presence of the ligand and the concerted motion of the ligand and a large part of the RNA binding site is necessary to achieve the final low-energy binding state.     

Macroevolution: dynamics of diversity

The fossil record typically exhibits very dynamic patterns of innovation, diversification and extinction. In contrast, molecular phylogenies suggest smoother patterns of evolutionary change. Several new studies reconcile this difference and reveal more about the mechanisms behind macroevolutionary change.     

Studying reactive processes with classical dynamics: rebinding dynamics in MbNO

A new surface-crossing algorithm suitable for describing bond-breaking and bond-forming processes in molecular dynamics simulations is presented. The method is formulated for two intersecting potential energy manifolds which dissociate to different adiabatic states. During simulations, crossings are detected by monitoring an energy criterion. If fulfilled, the two manifolds are mixed over a finite number of time steps, after which the system is propagated on the second adiabat and the crossing is carried out with probability one. The algorithm is extensively tested (almost 0.5 mus of total simulation time) for the rebinding of NO to myoglobin. The unbound surface (Fe...NO) is represented using a standard force field, whereas the bound surface (Fe-NO) is described by an ab initio potential energy surface. The rebinding is found to be nonexponential in time, in agreement with experimental studies, and can be described using two time constants. Depending on the asymptotic energy separation between the manifolds, the short rebinding timescale is between 1 and 9 ps, whereas the longer timescale is about an order of magnitude larger. NO molecules which do not rebind within 1 ns are typically found in the Xenon-4 pocket, indicating the high affinity of NO to this region in the protein.     

Structural dynamics of full-length retroviral integrase: a molecular dynamics analysis

HIV integrase catalyzes the integration between host and viral DNA and is considered as an interesting target for treating HIV. Knowledge of the complete structure of integrase is inevitable to describe the communicative inter-domain interactions affecting the HIV integration and disintegration process and hence the study on full-length integrase turns out to be an essential task. In this investigation, a structure of full-length integrase is designed to analyze the global dynamics of integrase dimer and monomers (with and without the C-terminal, 270-288 amino acids) for a period of 20?ns. The molecular dynamics analysis and the subsequent DynDom analysis reveal (i) a stable dynamics of dimeric CCD and NTD domains and (ii) CCD-α11-mediated rotational-cum-translational CTD motion as the functional dynamics of IN dimer. This observation supports that (i) aggregation enhances the integrase activity and (ii) flexible CTD for its cis and trans coordination with CCD. The role of C-loop over the dynamics of integrase is also explored, which unveils that the spatial arrangement of integrase domains is changed during dynamics in the absence of C-loop. In essence, here we report a C-loop-dependent structural dynamics of integrase and the active dynamics of integrase in dimer. Further studies on C-loop sensing mechanism and the multimerization of integrase would provide insight into HIV integration and disintegration processes. Supplementary material. Movies generated from molecular dynamics trajectory showing the CTD dynamics of IN structures (monomers with & without C-loop and dimer) are linked online to this article. The remaining supplementary data can be downloaded from the author's server at the URL http://ramutha.bicpu.edu.in .     

Superbinding: Spatio-temporal oscillatory dynamics

This paper presents superbinding, a concept that represents integrative oscillatory dynamics over the time and space axes. Principle of superposition describes integration over the temporal axis; selectively distributed and selectively coherent oscillatory neural populations describe integration over the spatial axis. Integrative activity is a function of the coherences between spatial locations of the brain; these coherences vary according to the type of sensory and or cognitive event and possibly the consciousness state of the species. Complex percepts and integrative activity in general that is achieved by superbinding supported by the neurons-brain theory may replace the Sherringtonian integrative brain function that is achieved through the single neuron doctrine.

Results of recent experiments related to the percept of the grandmother-face support our concept of super-synergy in the whole brain in order to explain manifestation of Gestalts and Memory-Stages. The strategies of the Grandmother paradigm may open new horizons in search of memories or evolving memories, and possibly provide relevant clinical applications.     

Successional state dynamics: A novel approach to modeling nonequilibrium foodweb dynamics

Communities and ecosystems are often far from equilibrium, but our understanding of nonequilibrium dynamics has been hampered by a paucity of analytical tools. Here I describe a novel approach to modeling seasonally forced food webs, called “successional state dynamics” (SSD). It is applicable to communities where species dynamics are fast relative to the external forcing, such as plankton and other microbes, diseases, and some insect communities. The approach treats succession as a series of state transitions driven by both the internal dynamics of species interactions and external forcing. First, I motivate the approach with numerical solutions of a seasonally forced predator-prey model. Second, I describe how to set up and analyze an SSD model. Finally, I apply the techniques to three additional models of two-species interactions: resource competition (r-K selection), facilitation, and flip-flop competition (where the competitive hierarchy alternates over time). This approach allows easy and thorough exploration of how dynamics depend on the environmental forcing regime, and uncovers unexpected phenomena such as multiple stable annual trajectories and year-to-year irregularity in successional trajectories (chaos).     

Measles metapopulation dynamics: a gravity model for epidemiological coupling and dynamics

Infectious diseases provide a particularly clear illustration of the spatiotemporal underpinnings of consumer-resource dynamics. The paradigm is provided by extremely contagious, acute, immunizing childhood infections. Partially synchronized, unstable oscillations are punctuated by local extinctions. This, in turn, can result in spatial differentiation in the timing of epidemics and, depending on the nature of spatial contagion, may result in traveling waves. Measles epidemics are one of a few systems documented well enough to reveal all of these properties and how they are affected by spatiotemporal variations in population structure and demography. On the basis of a gravity coupling model and a time series susceptible-infected-recovered (TSIR) model for local dynamics, we propose a metapopulation model for regional measles dynamics. The model can capture all the major spatiotemporal properties in prevaccination epidemics of measles in England and Wales.     

Wasp dynamics: A colony model

Social wasps are significant pests in many parts of the world, constituting a threat to human health and indigenous fauna as well as a commercial cost to industries such as beekeeping. In New Zealand Vespula vulgaris and V. germanica are significant environmental pests in large areas of native forest and, while limited chemical control is possible, for many areas there is no practical control option available. As part of a larger- scale ecological investigation into wasp biology and control, a within-colony model has been developed. The model is a simulation of intermediate complexity for which the driving relationships are drawn from an extensive field data set and published information. Although the model is conceptually similar to previous models and yields similar parameter values and output, it is mechanistically different. In particular, two new mechanistic relationships are derived: (1) the rate at which workers build cells is related to the larva:worker ratio; and (2) the rate at which the queen lays eggs is related to the number of worker-sealed brood present in the colony. Sensitivity analysis supports a possible role for queen quality in colony dynamics although other factors may also be involved. Also, sensitivity analysis results in model behaviour that is different to previous models; a result of its more mechanistic relationships. The model is intended as a tool to improve our understanding of wasp ecology and help develop effective strategies for wasp control.     

Quantitative character dynamics: Gametic model

A gametic model of quantitative character dynamics is introduced that fills the gap between the two existing models: genic and zygotic/phenotypic. In this model, a gamete is treated as the elementary unit of evolution, all biological processes at the levels below gametic remain unspecified, and a gamete is characterized by its effect on the quantitative character rather than by the genotype. The hereditary and developmental processes are accounted for in a generalized form by gametogenetic and developmental functions defined for a pair of gametic effects representing an individual. A parameterization of these functions is suggested that imposes constraints on the heredity of quantitative characters similar to the constraints imposed by traditional genic models. It is shown that this parameterization can be derived for some polygenic additive models. General expressions for the dynamics of the mean and variance of additive quantitative characters are obtained, and the dynamics under random mating for sex-independent, sex-controlled, and sex-linked characters are considered. Comparisons with the dynamics predicted by genic models are made.     

Population dynamics: Limits of predictability

Problems related to the complex pattern of ecosystem dynamics are discussed. Examples of studies on the complex population dynamics are considered, including those of plankton populations in a spatially heterogeneous environment and of an agroecosystem invaded by pests resistant to Bt toxins produced by genetically modified insecticidal crops.